Pyrene derivatives

ABSTRACT

The present invention relates to compounds of formula (I) 
     
         ArCH.sub.2 R.sup.1                                         (I) 
    
     or a monomethyl or a monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 30 carbon atoms in total); ethers, esters thereof; acid addition salts thereof; wherein Ar is a pyrene or substituted pyrene ring system; R 1  contains not more than eight carbon carbon atoms and is a group ##STR1## wherein m is 0 or 1; R 5  is hydrogen; 
     R 6  and R 7  are the same or different and each is hydrogen or C 1-3  alkyl optionally substituted by hydroxy; 
     R 8  and R 9  are the same or different and each is hydrogen or C 1-3  alkyl; ##STR2##  is a five- or six-membered saturated carbocyclic ring; R 10  is hydrogen, methyl or hydroxymethyl; 
     R 11 , R 12  and R 13  are the same or different and each is hydrogen or methyl; 
     R 14  is hydrogen, methyl, hydroxy, or hydroxymethyl.

This application is a continuation, of application Ser. No. 661,801, filed Oct. 17, 1984, and now abandoned which is a continuation-in-part of application Ser. No. 499,330, filed May 31, 1983 and now abandoned.

The present invention relates to polycyclic aromatic alkanol derivatives which have been found to have biocidal activity. More specifically the invention concerns aminoalkanol derivatives containing a polycarbocyclic aromatic ring system, methods for the synthesis thereof, pharmaceutical formulations thereof, novel intermediates therefor, pharmaceutical formulations thereof and the use thereof as biocidal agents, particularly antitumor agents.

Accordingly, in a first aspect, the present invention provides a compound of the formula (I):

    ArCH.sub.2 R.sup.1                                         (I)

or a monomethyl or monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 30 carbon atoms in total); ethers, esters thereof; acid addition salt thereof;

wherein

Ar is a pyrene ring optionally substituted by one or two substituents (the substituents will contain not more than four carbon atoms in total when taken together being the same or different and are selected from halogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionally substituted by hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl or C₁₋₂ alkoxy; a group S(O)_(n) R² wherein n is an integer 0, 1 or 2 and R² is C₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; or the pyrene ring is optionally substituted by a group NR³ R⁴ containing not more than 5 carbon atoms wherein R³ and R⁴ are the same or different and each is a C₁₋₃ alkyl group or NR³ R⁴ forms a five- or six-membered heterocyclic ring optionally containing one or two additional heteroatoms);

R¹ contains not more than eight carbon atoms and is a group ##STR3## wherein m is 0 or 1;

R⁵ is hydrogen;

R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₃ alkyl optionally substituted by hydroxy;

R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl; ##STR4## is a five- or six-membered saturated carbocyclic ring; R¹⁰ is hydrogen, methyl or hydroxymethyl;

R¹¹, R¹² and R¹³ are the same or different and each is hydrogen or methyl;

R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethyl.

Suitably ArCH₂ R¹ or a monomethyl or monethyl ether thereof contains not more than 28 carbon atoms in total.

Ar is suitably 1-pyrenyl, ##STR5## suitably m is 0, suitably R¹ is ##STR6## wherein R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH,

R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH;

R¹⁸ is hydrogen or methyl.

Preferably R¹⁶ is CH₂ OH or CH(CH₃)OH; R¹⁷ is hydrogen, methyl, ethyl or CH₂ OH.

Most preferably R¹ is a diol of the structure ##STR7## wherein R¹⁹ is hydrogen or methyl and R²⁰ is hydrogen, methyl or ethyl, preferably methyl. Acid addition salts included within the scope of the present invention are those of compound of formula (I) and ethers and esters thereof.

Esters and nonpharmaceutically useful acid addition salts of the compounds of the formula (I) are useful intermediates in the preparation and purification of compounds of the formula (I) and pharmaceutically useful acid addition salts thereof, and are therefore within the scope of the present invention. Thus, acid addition salts of the compounds of the formula (I) useful in the present invention include but are not limited to those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as isethionic (2-hydroxyethylsulfonic), maleic, malonic, succinic, salicylic, tartaric, lactic, citric, formic, lactobionic, pantothenic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene-2-sulfonic, and ascorbic acids, and amino acids such as glycine.

Acid addition salts particularly useful as biocidal agents are those that are pharmacologically and pharmaceutically acceptable. Thus, suitable acid addition salts include but are not limited to those derived from hydrochloric, methanesulfonic, ethanesulfonic, lactic, citric and isethionic acids.

The preferred pharmacologically and pharmaceutically acceptable acid addition salts are those that are soluble in solvents suitable for parenteral administration, for example, hydrochlorides, methanesulfonates and isethionates. Esters of compounds of formula (I) are derived from acids known to those skilled in the art to be suitable for ester formation, and are conveniently those derived from C₁₋₆ alkanoic acids or alkanoic acid derivatives, for example acetic acid, propionic acid, n-butyric acid and iso-butyric acid. The esters may be formed from all or only some of the hydroxy groups contained in the compounds of formula (I). Specific compounds within the scope of formula (I) include;

2-Methyl-2-((1-pyrenylmethyl)amino)propanol,

3-((1-Pyrenylmethyl)amino)propanol,

3-Methyl-2-((1-pyrenylmethyl)amino)butanol,

2-Ethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol,

2-((1-Pyrenylmethyl)amino)butanol,

2-((1-Pyrenylmethyl)amino)propanol,

1-((1-pyrenylmethyl)amino)-2-propanol,

2-Methyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol,

1-((1-Pyrenylmethyl)amino)-2-butanol,

2-Hydroxymethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol,

2-((1-Pyrenylmethyl)amino)-1,3-propanediol,

2-(((1-Pyrenylmethyl)amino)methyl)-2-propanol,

2-((1-Pyrenylmethyl)amino)ethanol,

4-((1-Pyrenylmethyl)amino)-2-butanol,

2-(((6-Bromo-1-byrenyl)methyl)amino)-2-methyl-1,3-propanediol and 2-(((8-Bromo-1-pyrenyl)methyl)amino)-1,3-propanediol,

2-Methyl-2-((4-pyrenylmethyl)amino)-1,3-propanediol,

(+-)(2R*,3S*)-2-((1-Pyrenylmethyl)amino)-2-methyl-1,3-butanediol,

2-Ethoxymethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol,

3-Methoxy-2-methyl-2-((1-pyrenylmethyl)amino)-1-propanol,

1α,2β,3α)-2-((1-Pyrenylmethyl)amino)-1,3-cyclohexanediol,

2-(((3-Ethyl-1-pyrenyl)-methyl)amino)-2-methyl-1,3-propanediol,

2-Isopropyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol and

2-(((8-Ethoxy-1-pyrenyl)methyl)amino)-2-methyl-1,3-propanediol;

ethers, esters thereof; acid addition salts thereof.

Of these specific examples of compounds of formula (I), the most preferred compound is 2-methyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol; ethers, esters thereof; acid addition salts thereof.

The compounds of formula (I) and their ethers, esters, and salts thereof may be prepared by any method known in the art for the preparation of compounds of analogous structure. Thus, the compounds of formula (I) may, for example, be prepared by any of the methods defined below.

1. The reduction of a compound of formula (II) ##STR8## Wherein R¹ -R⁴ are as hereinbefore defined or an appropriately protected derivative thereof followed by deprotection where appropriate.

The conditions and reagents for such a reaction are well known to those skilled in the art, and any such conditions/reagents may be employed. The conversion of (II) or suitably protected derivatives thereof may be carried out by a reducing agent followed by deprotection if necessary. The reduction conveniently carried out by a metal hydride such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, or by catalytic hydrogenation, conveniently by hydrogen in the presence of a metal catalyst such as palladium or platinum, or equivalent reagent as outlined by J. March, Advanced Organic Chemistry, 2nd ed., pages 819-820, McGraw Hill, New York, 1977. The reduction is suitably carried out with the compound of formula (II) in solution in an inert solvent or mixture of solvents compatible with the reducing agent, at a non-extreme temperature, or example, between 0° and 80° C., conveniently at room temperature.

In the case of lithium aluminum hydride and like reagents, suitable solvents include ethers (for example tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane) optionally in the presence of a hydrocarbon cosolvent (for example toluene, benzene or hexane).

In the case of sodium borohydride and like reagents, suitable solvents include alcohol (for example ethanol, methanol or isopropanol) optionally in the presence of a hydrocarbon cosolvent (for example toluene, benzene or hexane) or an ether cosolvent (for example diethylether or tetrahydrofuran).

In the case of sodium cyanoborohydride and like reagents, suitable solvents include those described for sodium borohydride and in the presence of an acid conveniently glacial acetic acid or ethanolic hydrochloric acid as outlined in, for example, R. Hutchins et al., Organic Preparations and Procedures International 11, 201 (1979).

In the case of catalytic hydrogenation, suitable solvents include alcohols (for example methanol and ethanol) optionally in the presence of a hydrocarbon cosolvent (for example toluene or benzene) or ether cosolvent (for example diethyl ether or tetrahydrofuran) optionally in the presence of an acid (for example glacial acetic acid or ethanolic hydrochloric acid) or in glacial acetic acid.

Protected derivatives of compounds of formula (II) are conveniently used when lithium aluminum hydride is employed as the reducing agent. Convenient protecting groups are compatible with the reducing agent utilized and are readily removed under nondestructive conditions, for example benzyl, tetrahydropyranyl and isopropylidene ethers.

It is often convenient not to isolate the compound of the formula (II) but to react a compound of the formula (III) with a compound of the formula (IV): ##STR9## wherein Ar and R¹ -R⁴ are as defined in (I), and reduce the compound of the formula (II) so formed in situ. The rection of the compounds of the formulae (III) and (IV) is again suitably carried out using conditions and reagents which are well known to those skilled in the art, for example in the presence of an acid, such as a sulfonic acid, i.e. p-toluenesulfonic acid, in an appropriate inert solvent, such as an aromatic hydrocarbon, for suitably toluene, with azeotropic removal of water followed by treatment with the reducing agent in an appropriate solvent, suitable ethanol or methanol. Alternatively, (II) formed under equilibrium conditions in appropriate solvents can be reduced in situ with an appropriate reducing agent, suitably sodium cyanoborohydride.

The compound of formula (III) may be in the form of a protected aldehyde, for example an acetal, which liberates the aldehyde function under the reaction conditions.

In turn, a compound of formula (III) can be synthesized by reacting the appropriate polycyclic aromatic hydrocarbon with a formylating agent such as that generated by the reaction between SnCl₄ and Cl₂ CHOCH₃ or equivalent reagents, for example, according to the method of A. Reiche et al., Chem. Ber. 93, 88 (1960), or with other standard formylating reagents/procedures known to the art, for example, the Gatterman-Koch reaction (CO/HCl/AlCl₃ /CuCl), the Gatterman reaction (HCN/HCl/ZnCl₂), and the Vilsmeier reaction (POCl₃ /PhN(Me)CHO or POCl₃ /Me₂ NCHO) (J. March, vide supra pages 494-497).

The compounds of the formula (III) may also be prepared from an appropriate polycyclic aromatic hydrocarbon substituted by a suitable functional group such as CH₂ OH, CHBr₂, CH₃, COCH₃, COOH, or CN, and converting this functional group to an aldehyde group by methods well known to those skilled in the art.

Where the polycyclic aromatic ring bears substituents, the compound of formula (III) may be prepared by a variety of methods known in the art of organic chemistry depending on the nature of the substituent on the polycyclic ring. For example, if the substituent(s) is a halogen, the starting materials may be prepared by direct treatment of the polycyclic aromatic hydrocarbon with a halogenating agent (e.g. Cl₂, Br₂, or SO₂ Cl₂) or directly by such routes as the Sandmeyer reaction (H. H. Hodgson, Chem. Rev. 40, 251 (1947). If the substituent(s) is alkyl, the polycyclic aromatic hydrocarbon may be reacted with the appropriate reagents under Friedel-Crafts reaction conditions (G. A. Olah, Friedel Crafts and Related Reactions, Vols. 1-3, Interscience, New York, NY, 1963-1965).

The compounds of the formula (IV) also may be prepared by methods known in the art, for example, by the reaction of compound NO₂ CH₂ R² with an appropriate aldehyde, conveniently acetaldehyde or formaldehyde (as in B. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940)) followed by reduction (as outlined in J. March, vide supra, pages 1125-1126), conveniently by hydrogen and a metal catalyst (for example, a platinum containing catalyst) in an appropriate solvent, conveniently glacial acetic acid.

2. The reduction of a compound of the formula (V) ##STR10## wherein Ar and R¹ -R⁴ are as hereinbefore defined and the hydroxy groups are optionally protected, followed by deprotection of the hydroxy groups where appropriate. The reduction may be carried out by standard reducing agents known for carrying out this type of reduction (as outlined in J. March, vide supra, page 1122), for example, a hydride reagent such as lithium aluminium hydride in an inert solvent, such as an ether, i.e. tetrahydrofuran, at a non-extreme temperature, for example, at between 0° and 100° C. and conveniently at the reflux temperature of the ether.

The compound of the formula (V) may be formed by the reaction of the appropriate acid (ArCOOH) or a suitable reactive acid derivative thereof as outlined in J. March, vide supra, pages 382-390) for example, an acid halide in an inert solvent, with an amine of the formula (IV) in which the hydroxy groups are optionally protected, for example, when the compound of the formula (IV) is a diol, by an isopropylidene group. The compound of the formula (V) so formed is suitably reduced in situ and deprotected if necessary to give a compound of formula (I). The compounds of the formula ArCOOH can be prepared by methods well known to those skilled in the art.

3. The reaction of a compound ArCH₂ L (wherein Ar is as hereinbefore defined and L is a leaving group), with a compound of the formula (IV) as hereinbefore defined. Suitable leaving groups are those defined by J. March, vide supra pages 325-331, and include halogens such as chlorine or bromine and sulfonic acid derivatives such as p-toluenesulfonate. The reaction is suitably carried out in an appropriate solvent, such as a dipolar aprotic solvent or alcohol at a non-extreme temperature, for example 50°-100°. The compounds of the formula ArCH₂ L can be prepared by methods well known to those skilled in the art.

There is therefore provided, as a further aspect of the invention, a method for the preparation of a compound of formula (I) comprising any method known for the preparation of analogous compounds, in particular those methods defined in (1) to (3) hereinabove.

The compounds of this invention have biocidal activity, e.g. are toxic to certain living cells which are detrimental to mammals, for example pathogenic organisms and tumor cells.

This toxicity to pathogenic organisms has been demonstrated by activity against viruses (e.g. Herpes simplex 1/vero), fungi (e.g. Candida albicans), protozoa (e.g. Eimeria tenella and Trichomonas vaginalis), bacteria (e.g. Mycoplasma smegmatis and Streptococcus pyogenes), and helminths (e.g. Nippostrongylus brasiliensis and Brugia pahangi). The antitumor activity of compounds of formula (I) has been demonstrated in a number of recognized screens and primarily by activity against ascitic P388/O leukemia.

Preferred compounds of the formula (I) are those which have antitumor activity. The activity against ascitic tumors, including P388/O, is evidenced by reduction of tumor cell number in mammals (for example, mice bearing ascitic tumors) and their consequent increase in survival duration as compared to an untreated tumor bearing control group. Antitumor activity is further evidenced by measurable reduction in the size of solid tumors following treatment of mammals with the compounds of this invention compared to the tumors of untreated control tumor bearing animals. Compounds of formula (I) are active against murine tumors such as lymphocytic leukemia P388/O, lymphocytic leukemia L1210, melanotic melanoma B16, P815 mastocytoma, MDAY/D2 fibrosarcoma, colon 38 adenocarcinoma, M5076 rhabdomyosarcoma and Lewis lung carcinoma.

Activity in one or more of these tumor tests has been reported to be indicative of antitumor activity in man (A. Goldin et al. in Methods in Cancer Research ed. V. T. DeVita Jr. and H. Busch, 16 165, Academic Press, New York 1979).

There are sublines of P388/O which have been made resistant to the following clinically useful agents: cytosine arabinoside, doxorubicin, cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil, actinomycin D, cis-platin and bis-chloroethylnitrosourea. Compounds of this invention show potent activity against these drug-resistant tumors using the procedure for P388/O.

Compounds of formula (I) have also been found to be active against human tumor cells in primary cultures of lung, ovary, breast, renal, melanoma, unknown primary, gastric, pancreatic, mesothelioma, myeloma, and colon cancer. (As used herein "cancer" is to be taken as synonymous with "malignant tumor" or more generally "tumor" unless otherwise noted.) This is a procedure in which the prevention of tumor cell colony formation, i.e. tumor cell replication, by a drug has been shown to correlate with clinical antitumor activity in man (D. D. Von Hoff et al., Cancer Chemotherapy and Pharmacology 6, 265 (1980); S. Salmon and D. D. Von Hoff, Seminars in Oncology, 8, 377 (1981)).

Compounds of formula I which have been found to have antitumor activity intercalate in vitro with DNA (this property is determined by viscometric methods using the procedure of W. D. Wilson et al., Nucleic Acids Research 4, 2697 (1954)) and a log P as calculated by the method of C. Hansch and A. Leo in Substituent Constants for Correlation Analysis in Chemistry and Biology, John Wiley and Sons, New York, 1979, lying in the range between -2.0 and +2.5.

As has been described above, the compounds of the present invention are useful for the treatment of animals (including humans) bearing susceptible tumors. The invention thus further provides a method for the treatment of tumors in animals, including mammals, especially humans, which comprises the administration of a clinically useful amount of compound of formula (I) in a pharmaceutically useful form, once or several times a day or other appropriate schedule, orally, rectally, parenterally, or applied topically.

In addition, there is provided as a further, or alternative, aspect of the invention, a compound of formula (I) for use in therapy, for example as an antitumor agent.

The amount of compound of formula (I) required to be effective as a biocidal agent will, of course, vary and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the condition being treated, the route of administration, and nature of the formulation, the mammal's body weight, surface area, age and general condition, and the particular compound to be administered. A suitable effective antitumor dose is in the range of about 0.1 to about 120 mg/kg body weight, preferably in the range of about 1.5 to 50 mg/kg, for example 10 to 30 mg/kg. The total daily dose may be given as a single dose, multiple doses, e.g., two to six timers per day or by intravenous infusion for selected duration. For example, for a 75 kg mammal, the dose range would be about 8 to 9000 mg per day, and a typical dose would be about 2000 mg per day. If discrete multiple doses are indicated, treatment might typically be 500 mg of a compound of formula I given 4 times per day in a pharmaceutically useful formulation.

While it is possible for the active compound (defined herein as compound of formula (I), or ether, ester, or salt thereof) to be administered alone, it is preferable to present the active compound in a pharmaceutical formulation. Formulations of the present invention, for medical use, comprise an active compound together with one or more pharmaceutically acceptable carriers thereof and optionally other therapeutical ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The present invention, therefore, further provides a pharmaceutical formulation comprising a compound of formula (I) (in the form of the free base, ether, or ester derivative or a pharmaceutically acceptable acid addition salt thereof) together with a pharmaceutically acceptable carrier therefore.

There is also provided a method for the preparation of a pharmaceutical formulation comprising bringing into association a compound of formula (I) an ether, ester, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefore.

While the antitumor activity of the compounds of formula (I) is believed to reside in the free base, it is often convenient to administer an acid addition salt of a compound of formula (I).

The formulations include those suitable for oral, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred are those suitable for oral or parenteral administration.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into assocation with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.

A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredients. Such accessory ingredient(s) may include flavorings, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppository with a conventional carrier such as cocoa butter.

Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient. Such formulations suitably comprise a solution of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that is isotonic with the blood of the recipient. Thus, such formulations may conveniently contain distilled water, 5% dextrose in distilled water or saline and a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that has an appropriate solubility in these solvents, for example the hydrochloride, isethionate and methanesulfonate salts, preferably the latter.

Useful formulations also comprise concentrated solutions or solids containing the compound of formula (I) which upon dilution with an appropriate solvent give a solution suitable for parenteral administration as above.

In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.

The following examples are provided by the way of illustration of the present invention and should in no way be construed as a limitation thereof.

GENERAL COMMENTS

All solvents were reagent grade and used without further purification with the following exceptions. THF was dried by distillation from Na/K alloy under nitrogen (N₂) and used immediately. Toluene (PhCH₃) was distilled from CaH₂ under N₂ and stored over 3 Å molecular sieves. Chemicals used were reagent grade and used without purification unless noted. The full name and address of the suppliers of the reagents and chemicals is given when first cited. After this, an abbreviated name is used.

Preparative HPLC was carried out on a Water's Prep LC/System 500A machine using two 500 g silica gel (SiO₂) cartridges unless otherwise noted. Plugs of SiO₂ used for purifications were "flash chromatography" silica gel (Merck & Co., Inc., Merck Chemical Division, Rahway, N.J., 07065 silica gel 60, 230-400 mesh). In this procedure, an appropriate volume sintered glass funnel was filled approximately 3/4 full with the SiO₂ and packed evenly by tapping the outside of the funnel. A piece of filter paper was then placed on top of the SiO₂ and a solution of the material to be purified applied evenly to the top. Gentle suction through a filter flask moved the eluting solvent through the plug rapidly. The appropriate size fractions were combined as needed and further manipulated.

General procedures are described in detail. Analogous procedures show melting point (mp), recrystallization solvents, and elemental analyses (all elements analyzing within a difference of ≦0.4% of the expected value). Any changes to the procedure such as solvent, reaction temperature, reaction time, or workup are noted.

NMR (¹ H, ¹³ C), IR, MS data of all new products were consistent with the expected and proposed structures. The positions assigned to structural isomers were unequivocally determined by a number of NMR techniques. All final products were dried in a vacuum oven at 20 mm Hg pressure at the temperature indicated overnight (12-16 h). All temperatures are in degrees Celsius. Other abbreviations that were used: room temperature (RT), absolute (abs.), round bottom flask (RB flask), minutes (min), hours (h).

EXAMPLE 1 2-Methyl-2-((1-pyrenylmethyl)aminio)-1,3-propanediol 1A. 2-Methyl-2-((1-pyrenylmethyl)amino-1,3-propanediol hydrochloride

To a 2 L Erlenmeyer flask was added 1-pyrenecarbaldehyde (Aldrich Chemical Co., Milwaukee, WI, 53201, 115.1 g, 0.5 mol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 52.57 g, 0.5 mol), p-toluenesulfonic acid.H₂ O (Eastman Kodak Co., Rochester, N.Y., 14650, 1 g, 5 mmol), and PhCH3 (500 mL). The mixture was warmed to reflux for a few minutes and H₂ O (˜10 mL) was driven off. The resulting yellow solutin was allowed to cool to RT, diluted with abs. EtOH (500 mL) and stirred overnight. NaBH₃ CN (Aldrich, 95%, 15.71 g, 0.25 mol) was added to the reaction. After the NaBH₃ CN dissolved, an indicator (bromocresol green, Eastman, 5 mg) was added. To the resulting blue solution was added 5 drops of 1M ethanolic HCl every 15 min. After 3 days the indicator turned green then yellow and a voluminous white precipitate was present in the flask. To the flask was then added 1M ethanolic HCl (50 mL). The reaction was diluted to 4 L with abs. Et₂ O and stirred for 1 h. The precipitate was then collected by filtration through a medium porosity glass fritted funnel, washed with Et₂ O (2 L), and pressed dry. The filter cake was washed thoroughly with 20% HCl (5×250 mL), pressed dry and then washed with CH₂ Cl₂ (4×500 mL), pressed and sucked dry. The white solid was dried at 60° overnight. The off-white crude material (149 g) was dissolved in hot H₂ O (2.5 L) containing 20 mL of conc. HCl and decolorized with 20 g of Calgon® (trademark of Calgon Corp., a subsidiary of Merck & Co., Pittsburgh, PA, 15230) brand of activated charcoal, filtered through a pad of Celite® (trademark of Johns Manville Co., Denver, CO, 80110) brand of filter-aid to give a total of 2.8 L of clear colorless solution. The volume of the solution was reduced to 1.8 L. The solution was allowed to cool to RT, and then was placed in a refrigerator overnight. The white solid which formed overnight was collected by filtration, dried overnight at 60°, and recrystallized from EtOH/Et₂ O to give 104 g (56%) of 2-methyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride mp 231°-230°, (C, H, Cl, N).

1B. 2-Methyl-2-((1-pyrenylmethyl)amino-1,3-propanediol methanesulfonate

To a solution of 1A (35.58 g, 0.1 mol) in CH₃ OH (500 mL) was added 1N NaOH (110 mL) dropwise over 15 min. The mixture became hard to stir and was diluted with H₂ O (1.5 L). The white solid which formed was filtered and washed successively with warm H₂ O (3×500 mL), then CH₃ OH (200 mL), then Et₂ O (3×500 mL). It was then dried overnight in a vacuum. Final yield of material was 25.4 g (79.5%) which was used without further purification.

The free base (17.5 g, 54.8 mmol) was suspended in CH₃ OH, cooled, and treated slowly with methanesulfonic acid (Aldrich, 5.27 g, 3.56 mL, 54.8 mmol). The mixture was stirred at RT for 10 min, warmed to reflux, filtered through a sintered glass funnel, then diluted with Et₂ O (3.5 L). An oil formed which then crystallized within a few minutes. The solid was then filtered and recrystallized 2× from CH₃ OH/Et₂ O to give after drying 19.1 g (84.0%) of 2-methyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol methanesulfonate mp 184°-186°, (C, H, N, S).

EXAMPLE 2 2-Methyl-2-((1-pyrenylmethyl)amino)propanol 2A. 2-Methyl-2-((1-pyrenylmethyl)amino)propanol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 2-methyl-2-amino-1-propanol (Aldrich) gave 2-methyl-2-((1-pyrenylmethyl)amino)propanol hydrochloride mp 253.5°-254° (dec), (95% EtOH), (C, H, Cl, N).

2B. 2-Methyl-2-((1-pyrenylmethyl)amino)propanol

Using the first part of the method in 1B, 2A gave 2-methyl-2((1-pyrenylmethyl)amino) propanol free base mp 135°-136°, (95% EtOH), (C, H, N).

EXAMPLE 3 3-((1-pyrenylmethyl)amino)propanol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 3-amino-1-propanol (Aldrich) gave 3-((1-pyrenylmethyl)amino)propanol hyrochloride mp 194°-195° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 4 3-Methyl-2-((1-pyrenylmethyl)amino)butanol hydrochloride

Using the reductive aminatin procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 3-methyl-2-aminobutanol (Aldrich) gave 3-methyl-2-((1-pyrenylmethyl)amino)butanol hydrochloride mp 246°-248° (dec), (95% EtOH), (C, H, Cl, N).

EXAMPLE 5 2-Ethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol 5A. 2-Ethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 2-amino-2-ethyl-1,3-propanediol (Aldrich) gave 2-ethyl-2-((1-pyrenylmethyl)amino)-1,3-propanedol hydrochloride mp 225°-226.5° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

5B. 2-Ethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol methanesulfonate

Using the procedure described in 1B, 5A gave 2-ethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol methanesulfonate mp 200°-201°, (CH₃ OH/Et₂ O), (C, H, N, S).

EXAMPLE 6 2-((1-Pyrenylmethyl)amino)butanol hydrochloride

Using the reductive amination procedure described in 1A, 1-pyrenecarbaldehyde (Aldrich) and 2-amino-1-butanol (Aldrich) gave 2-((1-pyrenylmethyl)amino)butanol hydrochloride mp 224°-225.5° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 7 2-((1-Pyrenylmethyl)amino)propanol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 2-amino-1-propanol (Aldrich) gave 2-((1-pyrenylmethyl)amino)propanol hydrochloride mp 230°-232° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 8 1-((1-pyrenylmethyl)amino)-2-propanol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and dl-1-amino-2-propanol (Aldrich) gave 1-((1-pyrenylmethyl)amino)-2-propanol hydrochloride mp 217°-218° (dec), (abs. EtOH), (C, H, CL, N).

EXAMPLE 9 1-((1-Pyrenylmethyl)amino)-2-butanol hydrochloride

Using the procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 1-amino-2-butanol (Aldrich) gave 1-((1-pyrenylmethyl)amino)methyl)-2-butanol hydrochloride, mp 237°-238° (dec), (abs. EtOH), (C, H, Cl, N).

EXAMPLE 10 2-Hydroxymethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and tris(hydroxymethyl)aminomethane (Aldrich) gave 2-hydroxymethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride mp 232°-234° (dec), (CH₃ OH/Et₂ O), (C, H, Cl, N).

EXAMPLE 11 2-((1-Pyrenylmethyl)amino)-1,3-propanediol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 2-amino-1,3-propanediol (Sigma Chemical Company, St. Louis, MO, 63178) gave 2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride mp 211°-213° (dec), (CH₃ OH/Et₂ O), (C, H, Cl, N).

EXAMPLE 12 2-(((1-Pyrenylmethyl)amino)methyl)-2-propanol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 1-amino-2-methyl-2-propanol (Aldrich) gave 2-(((1-pyrenylmethyl)amino)methyl-2-propanol hydrochloride, mp 225°-226.5° (dec), (abs. EtOH), (C, H, Cl, N).

EXAMPLE 13 2-((1-Pyrenylmethyl)amino)ethanol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 2-aminoethanol (Aldrich) gave 2-((1-pyrenylmethyl)amino)ethanol hydrochloride mp 202°-203° (dec), (95% EtOH) (C, H, Cl, N).

EXAMPLE 14 4-((1-Pyrenylmethyl)amino)-2-butanol hydrochloride

Using the reductive amination procedure outlined in 1A, 1-pyrenecarbaldehyde (Aldrich) and 4-amino-2-butanol (Aldrich) gave 4-((1-pyrenylmethyl)amino)-2-butanol hyrochloride mp 204°-206°, (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 15 2-Acetoxymethyl-1,3,-O-diacetyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol

To a suspension of 2-hydroxymethyl-2-((1-pyrenylmethyl)amino)-1, 3 -propanediol hydrochloride (10, 2.50 g, 6.7 mmol) in 150 mL of dry THF was added 5 mL of acetylchloride (Aldrich, excess). The mixture was heated at reflux for 2 h, poured into 500 mL of cold 5% NaHCO₃ and then extracted with EtOAc (3×500 mL). The extracts were combined, washed with satd. NaCl solution, dried (K₂ CO₃) and concentrated to 200 mL. This solution was boiled with a small amount of decolorizing charcoal and applied to a small plug (50 g) of SiO₂. Elution with 1 of EtOAc followed by concentration to 100 mL and dilution with 400 mL of hexane gave a crystalline product. This solid was collected by filtration and dried to give 2.73 g (88%) of 2-acetoxymethyl-1,3-O-diacetyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol mp 150°-150.5°, (C, H, N).

EXAMPLE 16 2-Ethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol diacetate

Using the procedure described for 15, 2-ethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride (5A) gave 2-ethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol diacetate mp 106°-107°, (hexane), (C, H, N).

EXAMPLE 17 2-(((6-Bromo-1-pyrenyl)methyl)amino)-2-methyl-1,3-propanediol and 2-((8-Bromo-1-pyrenylmethyl)amino)-2-methyl-1,3-propanediol 17A. 6 and 8-Bromopyrene-1-carbaldehyde

1-Bromopyrene was prepared by the procedure of W. H. Gumprecht, Org. Syn. Coll. Vol. V, 147 (1973), and formylated using the procedure of A. Reiche et al., Chem. Ber. 93, 88 (1960) affording an approximately 1:1 ratio of 6- 8-bromopyrene-1-carbaldehydes mp 168°-181°, (PhCH₃ /CH₃ OH), (C, H, Br). This mixture was used without further purification.

17B. 2-((6-Bromo-1-pyrenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride and 2-((8-Bromo-1-pyrenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride

Using the reductive amination procedure described in 1A, the mixture of 6- and 8-bromopyrene-1-carbaldehydes (17A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a mixture of 2-((6-bromo-1-pyrenylmethyl)amino)-2-methyl-1,3-propanediol hydrochloride and 2-((8-bromo-1-pyrenylmethyl)amino)-2-methyl-1,3-propanediol hyrochloride (1:1) mp 219°-220°, (EtOH/Et₂ O), (C, H, Br, Cl, N).

EXAMPLE 18 2-Methyl-2-((1-pyrenylemthyl)amino)-1,3-propanediol diacetate

Using the procedure described for 15, 2-methyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride (1A) gave 2-methyl-2-(1-pyrenylmethyl)amino)-1,3-propanediol diacetate mp 91°-92°, (hexane), (C, H, N).

EXAMPLE 19 2-Methyl-2-((4-pyrenylmethyl)amino)-1,3-propanediol 19A. 1,2,3,6,7,8-Hexahydro-4-pyrenecarbaldehyde

Using the formylation procedure of A. Reiche et al., Chem. Ber. 93, 88 (1960), 1,2,3,6,7,8 hexahydropyrene (Aldrich) gave 1,2,3,6,7,8-hexahydro-4-pyrenecarbaldehyde mp 102.5°-105°, (PhCH₃ /hexane), (C, H), (lit. mp 116°, J. -P. Hoeffinger et al., Bull. Soc. Chim. Fr. 3099 (1969)).

19B. 4-pyrenecarbaldehyde

1,2,3,6,7,8-Hexahydro-4-pyrenecarbaldehyde (19A, 11.81 g, 50 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (Aldrich, 39.75 g, 0.175 mol) were refluxed for 4 h in 1 L of PhCH₃. The reaction mixture was cooled and then filtered. The filtrate was washed with 2N NaOH (3×500 mL), satd. NaCl solution (2×500 mL), dried (Na₂ SO₄), and passed through a plug of SiO₂ (200 g). The solvent was then removed to give a bright yellow solid that was dried at 50° to give 8.91 g (77%) of 4-pyrenecarbaldehyde which was used without further purification. An analytical sample had mp 172°-174°, (CH₂ Cl₂ /hexane), (C, H), (lit. mp 177°-179°, Y. E. Gerasimenko and I. N. Shevcbuk, Zh. Org. Khim. 4 2198 (1968)).

19C. 2-Methyl-2-((4-pyrenylmethyl)amino)-1,3-propanedol hydrochloride

Using the reductive amination procedure outlined in 1A, 4-pyrenecarbaldehyde (19B) and 2-amino-2-methyl-1,3-propanedol (Aldrich) gave 2-methyl-2-((4-pyrenylmethyl)amino)-1,3-propanediol hydrochloride.1/4H₂ O mp 225°-227° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 20 (+-)(2R*,3S*)-2-((1-Pyrenylmethylamino)-2-methyl-1,3-butanediol 20A. (+-)(2R*,3S*)-2-Methyl-2-nitro-1,3-butanediol and 20B. (+-)(2R*,3R*)-2-Methyl-2-nitro-1,3-butanediol

To a mixture of 2-nitro-1-propanol (Aldrich, 63.0 g, 0.060 mol) and acetaldehyde (Eastman, 39.6 g, 0.90 mol) cooled in an ice bath under N₂ was added cold H₂ O (40 mL) and calcium hydroxide (200 mg). The mixture was allowed to warm to RT over 2 h and the stirred for 68 h. The resulting solution was neutralized with excess solid CO₂. The mixture was stirred for 1 h before filtration through a Millipore filter (Millipore Corp., Bedford, MA, 01730). The filtrate was then concentrated under vacuum at 35°. The residue, a viscous syrup which partially crystallized on drying under vacuum (0.1 mm, RT, 48 h), was trituarated with cold Et₂ O (35 mL). Solid white crystals which formed were collected by filtration, washed with cold Et₂ O (3×15 mL) and dried under vacuum (0.1 mm, RT) to give 34.1 g of material, judged by NMR to be (+)(2R*, 3S*)-2-methyl-2-nitro-1,3-propanediol (20A) (purity >97%, racemic). After recrystallization, the diastereomeric purity was >99%, mp 78.5°-81° (lit. 78°; cf. Beil 1, 482 in Henry, Bull. Soc. Chim. Fr. [3] 15, 1224), (C, H, N).

The original filtrate (including washing) was concentrated under vacuum to a pale yellow liquid which was subjected to flash chromatography as follows: The sample was mixed with hexane:EtOAc (2:1, 100 mL) and added to a column of dry SiO₂ (1.5 kg). The column was eluted with hexane:EtOAc (2:1, 12 L) then hexane:EtOAc (1:1, 6 L) while 500 mL fractions were collected. Appropriate fractions were combined. Pure product was found in the final 8 L; yield, 38.7 g of viscous syrup, judged by NMR to be a 1:1 mixture of the two racemic diastereomers (20A and 20B), (C, H, N).

This and another batch of the 1:1 diasteriomeric mixture (prepared as described above) were combined (67 g, total) and subjected to successive liquid-liquid partitioning between H₂ O and EtOAc to give pure samples (˜99% on the basis of NMR and HPLC (Hamilton PRP-1 column using 3.5% aqueous acetonitrile as the mobile phase)) of (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-propanediol (20A) (24.9 g, k'=4.3, C, H, N) and (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (20B) (15.8 g, k'=2.1, C, H, N, a colorless, viscous liquid).

20C. (+-)(2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane and 20D. (+-)(2R*,4S*,5S*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane

The relative configurations of these two diasteriomeric pairs (20A and 20B) were unequivocably assigned on the basis of comparative NMR analysis of the respective cyclic acetals derived from benzaldehyde. Thus, (20A) (1.49 g, 0.01 mol) and benzaldehyde (Mallinckrodt, 1.06 g, 0.01 mol) were condensed in benzene in the presence of a catalytic amount of p-toluenesulfonic acid with azeotropic removal of water (according to the method of H. Piotrowska, B. Serafin and T. Urbanski, Tetrahedron 109, 379 (1963)). After successive washing with satd. NaHCO₃ solution, drying (MgSO₄), filtration, and removal of the benzene by rotary evaporation, a pale yellow solid was obtained. A solution of this product in ethanol at 0° C. provided an oil which was isolated by decanting the mother liquor and drying under vacuum (0.1 mm, RT). The yield was 1.48 g (62%) of (+-)(2R*,4S*,5R*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane (20C) (C, H, N).

Similarly prepared from (20B) and benzaldehyde was (+-)(2R*,4S*,5S*)-4,5-dimethyl-5-nitro-2-phenyl-1,3-dioxane (20D) (74%) (C, H, N).

20E. (+-)(2R*,3R*)-2-Amino-2-methyl-1,3-butanediol acetate

To a solution of (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (20B, 22.1 g, 0.148 mol) in 95% EtOH (150 mL) was added glacial acetic acid (25 mL) and 10% Pd/C (MCB, 2.0 g). The reduction was carried out in a Parr apparatus at 50 psi of H₂ during a 48 h period at RT. The catalyst was removed by filtration through a Millipore® filter, and the solvent removed under vacuum (2 days). The viscous, colorless syrup was dissolved in abs. EtOH (30 mL). Dilution with abs. Et₂ O (300 mL) give a cloudy liquid which was placed in a refrigerator for two days. During this time, colorless crystals formed which were washed with Et₂ O and dried in a vacuum oven at RT for two days. The yield of (+-) (2R*,3R*)-2-amino-2-methyl-1,3-butanediol acetate was 25.6 g (97%) mp 117°-121°, (C, H, N).

20F. (+-)(2R*,3S*)-2-Amino-2-methyl-1,3-butanediol acetate

Using the procedure described for 20E, (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (20A) gave (+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediol acetate (93%) (C, H, N) mp 163°-165° C.

20G. (+-)(2R*,3S*)-2-((1-Pyrenylmethyl)amino)-2-methyl-1,3-butanediol hydrochloride

To a RB flask was added (+-)(2R*,3S*)-2-amino-2-methyl-1,3-butanediol acetate (20F) and an equimolar amount of sodium methoxide (MCB) and CH₃ OH (100 mL). After warming the solvent was removed by rotary evaporation and after addition of 1-pyrenecarbaldehyde (Aldrich) the reaction run following the normal reductive amination procedure outlined in 1A to give (+-)(2R*,3S*)-2-((1-pyrenylmethyl)amino)-2-methyl-1,3-butanediol hydrochloride mp 221°-222° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 21 2-Ethoxymethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol 21A. 3,5-Diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole

A mechanically stirred 60% dispersion of NaH in mineral oil (Alfa, 34.0 g, 0.85 mol) was washed with dry hexane to remove the oil and suspended in dry DMF (300 mL). To the mixture was added a solution of 3,5-diphenyl-1H,3H,5H-oxazolo(3,4-c)oxazole-7a(7H)-methanol (208.2 g, 0.7 mol, prepared by the method of J. Pierce et al., J. Amer. Chem. Soc. 73 2595 (1951)) in dry DMF (300 mL) keeping the reaction mixture between 30°-35°. The salt suspension was stirred at RT for 60 min, diluted with dry DMF (200 mL) to facilitate stirring, cooled, then treated with ethyl iodide (Aldrich, excess) at such a rate that the reaction temperature was between 20°-35°. The mixture was stirred at RT for 2 h, then cautiously treated with absolute EtOH (30 mL). The resulting mixture was diluted with Et₂ O (2.5 L) and the resulting solids removed by filtration. The solvent was then removed using a rotary evaporator to give 299.5 g of a yellow oil containing both starting material and desired product. A solution of the oil in chloroform was mixed with SiO₂ (200 g) and the solvent removed. The solid was then added to a column of SiO₂ (800 g). Elution with the EtOAc/hexane (1:3.5) gave 139.7 g (61.3%) of 3,5-diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole. An analytical sample was obtained by recrystallization from hexane, mp 83.5°-85.°, (C, H, N). The bulk of the material was used without further purification.

21B. 2-Amino-2-ethoxymethyl-1,3-propanediol hydrochloride 1/4H₂ O

3,5-Diphenyl-7a(7H)-ethoxymethyl-1H,3H,5H-oxazolo(3,4-c)oxazole (21A, 136 g, 0.42 mol) was dissolved in 6N HCl (400 mL) and the resulting solution stirred 1.5 h at RT. After extraction with Et₂ O (2×200 mL) to remove benzaldehyde, the aqueous solution was concentrated on a rotary evaporator to give a colorless oil. This was cooled in an ice bath to facilitate crystallization. The solid which formed was slurried with cold CH₃ CN, filtered, then washed with Et₂ O and dried in a vacuum oven at RT to give 71 g (89%) of 2-amino-2-ethoxymethyl-1,3-propanediol hydrochloride.1/4H₂ O mp 78°-79°, (C, H, Cl, N).

21C. 2-Ethoxymethyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride 1/3H₂ O

To a RB flask was added 2-amino-2-ethoxymethyl-1,3-propanediol hydrochloride.1/4H₂ O (21B) and an equimolar amount of sodium methoxide (MCB) and CH₃ OH (100 mL). After warming the solvent was removed by rotary evaporation and after addition of pyrene-1-carbaldehyde (Aldrich) the reaction run following the normal reductive amination procedure outlined in 20 G to give 2-ethoxymethyl-2-(((1-pyrenyl)methyl)amino)-1,3-propanediol hydrochloride.1/3H₂ O, mp 189°-190° (dec), (EtOH/Et₂ O), (C, H, Cl, N).

EXAMPLE 22 3-Methoxy-2-methyl-2-((1-pyrenylmethyl)amino)-1-propanol 22A. 4-Aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane

A solution of 2-amino-2-methyl-1,3-propanediol (Aldrich, 303.4 g, 3.0 mol), cyclohexanone (Fischer, 294.5 g, 3.0 mol) and PhCH₃ (400 mL) was refluxed for approximately 2 h with azeotropic removal of H₂ O. The material which crystallized from the PhCH₃ on cooling was recrystallized twice from hexane to give 444.4 g of 4-aza-3-hydroxymethyl-3-methyl-oxaspiro [4.5]decane (80%) mp 52°-54°, (C, H, N).

22B. 4-Aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane

A mechanically stirred 60% dispersion of NaH in mineral oil (Alfa, 75 g, 1.9 mol) was washed with dry hexane to remove the oil and suspended in dry DMF (200 mL). To the mixture was added a solution of 4-aza-3-hydroxymethyl-3-methyl-1-oxaspiro[4.5]decane (22A, 27.8 g, 1.5 mol) in dry DMF (200 mL) keeping the reaction mixture temperature between 30°-35°. Small amounts of DMF were added as necessary to facilitate stirring. The mixture was stirred at RT for 1.5 h, then cooled and treated with methyl iodide (Fisher, 234.2 g, 102.7 mL, 1.65 mol) keeping the reaction temperature between 20°-30°. The mixture was stirred 2 H at RT and slowly treated with absolute EtOH (40 mL), then diluted with dry Et₂ O (3 L). The reaction mixture was filtered and the solvent removed by rotary evaporation. The residue was then fractionally distilled to give 209.7 g (70.3%) of 4-aza-3-methoxymethyl-3-methyl-1-oxaspiro[4.5]decane as a colorless liquid bp 114°/14 mm, (C, H, N).

22C. 2-Amino-3-methoxy-2-methyl-1-propanol

A solution of 4-aza-3-methoxymethyl-3-methyl-1-oxaspiro(4.5)decane (22B, 299 g, 1.5 mol) and 6N HCl (500 mL) was refluxed for 60 min. On cooling, two layers formed, the upper one containing cyclohexanone was removed by extraction with Et₂ O (2×400 mL). The lower aqueous layer was concentrated on a rotary evaporator to give a syrup which then was treated with excess 50% NaOH. The resulting slurry was extracted with Et₂ O/CH₂ Cl₂ (2:1, 4×500 mL), then with CH₂ Cl₂ (500 mL). The solvent was removed by rotary evaporation to give 198 g of pale oil. Fractional distillation of this oil gave 166 g (93%) of 2-amino-3-methoxymethyl-1-propanol as a colorless oil, bp 94° C./17 mm, (C, H, N).

22D. 3-Methoxy-2-methyl-2-((7-pyrenylmethyl)amino)-1-propanol methanesulfonate 1/3H₂ O

Using the reductive amination procedure outlined in 20G, pyrene-1-carbaldehyde (Aldrich) and 2-amino-3-methoxy-2-methyl-1-propanol (22C) gave after workup using the procedure outlined in 1B 3-methoxy-2-methyl-2-((1-pyrenylmethyl)amino)-1-propanol methanesulfonate.1/3H₂ O mp 158°-160°, (EtOH/Et₂ O), (C, H, N, S).

EXAMPLE 23 (1α,2β,3α)-2-((1-Pyrenylmethyl)amino)-1,3-cyclohexanediol methanesulfonate 23A. (1α,2β,3α)-2-Amino-1,3-cyclohexanediol acetate

This compound was prepared by the method of F. Lichtenthaler (Ber. 96, 851 (1963), mp 175°-177°, (C, H, N), (lit 178°-179°, F. Lichtenthaler, Ber. 96, 845 (1963).

23B. (1α,2β,3α)-2-((1-Pyrenylmethyl)amino)-1,3-cyclohexanediol methanesulfonate

To a RB flask was added (1α,2β,3α)-2-amino-1,3-cyclohexanediol acetate (23A) and an equimolar amount of NaOCH₃ and CH₃ OH (100 mL). After warming, the solvent was removed by rotary evaporation, and after addition of 1-pyrenecarbaldehyde (Aldrich) the reaction run following the normal reductive amination procedure outlined in 22D to give (1α,2β,3α)-2-((1-pyrenylmethyl)amino)-1,3-cyclohexanediol methanesulfonate mp 257°-258° (dec), (CH₃ OH/Et₂ O), (C, H, N, S).

EXAMPLE 24 Isopropyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol 24A. 2-Isopropyl-2-nitro-1,3-propanediol

A solution of 2-methyl-1-nitropropane (38.7 g, 0.375 mol prepared by the procedure of N. Kornblum, B. Taube, and H. Ungnade, J. Am. Chem. Soc. 76, 3209 (1954) and NEt₃ (Eastman 3.79 g, 0.0375 mol) in CH₃ OH (50 mL) was added dropwise 37% aqueous formaldehyde solution (Mallinckrodt, 76.2 g, 0.938 mol), at a rate such that the reaction mixture temperature did not exceed 30°. After 72 h, the solution was concentrated under vacuum and the residue was dissolved in H₂ O (250 mL). The solution was continuously extracted for 1 h with CH₂ Cl₂ (1 L). The CH₂ Cl₂ solution was dried (MgSO₄), filtered, and concentrated to give 53.3 g (87%)of 2-isopropyl-2-nitro-1,3-propanediol a waxy, white solid mp 67°-72° (lit. mp 87°-88°, B. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940). In our hands this procedure failed to give the desired compound).

24B. 2-Amino-2-isopropyl-1,3-propanediol acetate

Using the procedure in 20E, 2-isopropyl-2-nitro-1,3-propanediol gave a 98% yield of 2-amino-2-isopropyl-1,3-propanediol acetate mp 155°-155.5°. H. S. Broadbent et al., J. Heterocyclic Chem., 13, 337 (1975) report the synthesis of this compound as the free base (mp 70°-72°).

24C. 2-Isopropyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride

Using the reductive amination procedure described for 20G, pyrene-1-carbaldehyde (Aldrich) and 2-amino-2-isopropyl-1,3-propanediol acetate (24B) gave 2-isopropyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride mp 244°-245° (dec), (CH₃ OH/Et₂ O), (C, H, N, Cl).

EXAMPLE 25 2-(((3-Ethyl-1-pyrenyl)methyl)amino)-2-methyl-1,3-propanediol

25A. 3-Ethylpyrene-1-carboxaldehyde

1-Ethylpyrene (Cambridge Chemical, Inc., 55 g, 0.239 mol) was formylated by the procedure of A. Reiche et al., Chem. Ber. 93, 88 (1960). The isomeric aldehyde product mixture (48.2 g, 0.187 mol) (which could not be purified by chromatography on SiO₂) was treated with LiBH₄ (Alfa-Ventron, 2 g, 0.09 mol) in THF (800 mL). After 12 h, the reaction mixture was poured into ice water and acidified to pH=2 with 1N HCl. The isomeric alcohol mixture isolated (48 g, 0.18 mol) was chromatographed by preparative HPLC using CH₂ Cl₂ as the eluting solvent. A poorly resolved, 3-component band resulted. The first component to elute was isolated by front-shaving and purified by recycling. The purified component (8.5 g) was treated directly with BaMnO₄ (Aldrich, 15.75 g, 0.61 mol) in CH₂ Cl₂ (400 mL). After 3 h of refluxing, the mixture was filtered and the solvent removed to give the crude aldehyde. This was purified by preparative HPLC using CH₂ Cl₂ as the eluting solvent to give 4.38 g (7%) of 3-ethylpyrene-1-carboxaldehyde mp 134°-135.5°, (C, H), (CH₂ Cl₂ /hexane).

25B. 2-(((3-Ethyl-1-pyrenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate.3/10H₂ O

Using the reductive amination procedure outlined in 22D, 3-ethylpyrenecarboxaldehyde (25A) and 2-methyl-2-amino-1,3-propanediol (Aldrich) gave 2-(((3-ethyl-1-pyrenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate.3/10H₂ O mp 216°-219° (dec), (EtOH/Et₂ O), (C, H, N, S).

EXAMPLE 26 2-(((8-Ethoxy-1-pyrenyl)methyl)amino)-2-methyl-1,3-propanediol 26A. 8-Ethoxypyrene-1-carboxaldehyde

Using the method of E. Profft and R. Biela, Chem. Ber., 94, 2374-82, 1-ethoxypyrene (Cambridge Chemical, Inc., 25 g, 0.101 mol) yielded an insoluble red formylation complex that was filtered from the reaction mixture and hydrolyzed. The crude aldehyde obtained (mp 102°-122°) was recrystallized 2× from CH₂ Cl₂ /hexane to yield 7.52 g (27%) of 8-methoxypyrene-1-carboxaldehyde mp 135°-136°, (lit 135.5°-136.5°, E. Profft and R. Biela, Chem. Ber. 94, 2374-82), (C, H).

26B. 2-(((8-Ethoxy-1-pyrenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate

Using the reductive amination procedure described in 22D, 8-ethoxypyrene-1-carbaldehyde (26A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((8-ethoxy-1-pyrenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate mp 202°-203° (dec), (EtOH/Et₂ O), (C, H, N, S).

Antitumor Screening Results

Methods for evaluating the antitumor activity of these compounds are essentially those used in the Tumor Panel by the Development Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, A. Goldin, et al., Methods in Cancer Research, Vol. XVI, p. 165, Academic Press (1979). Some modifications in dose level and schedule have been made to increase the testing efficiency.

EXAMPLE 27 Lymphocytic Leukemia P388/0 Test

CD2-F₁ mice, of the same sex, weighing 20±3 g, are used for this test. Control and test animals are injected intraperitoneally with a suspension of ˜10⁶ viable P388/0 tumor cells on day 0. In each test, several dose levels which bracket the LD₂₀ of the compound are evaluated; each dose level group contains 6 animals. The test compounds are prepared either in physiologic saline containing 0.05% Tween 80 or distilled water containing 5% dextrose and are administered intraperitoneally on days 1, 5, and 9 relative to tumor implant. Doses are on a mg/kg basis according to individual animals' body weights. The day of death for each animal is recorded, the median identified for each group and the ratios of median survival time for treated (T)/control (C) groups are calculated. The criterion for activity is T/C×100≧120%. Results of P388/0 testing are summarized in Table I below.

                  TABLE I                                                          ______________________________________                                         P388/0 SCREENING RESULTS                                                                             T/C × 100%                                         Compound of                                                                              Optimal Dose                                                                               (Excluding 30 Day                                        Example No.                                                                              (mg/kg)     Survivors)    LD.sub.20 A                                ______________________________________                                         2A        250         +168          170                                        2B        450         +145          450                                        3         120         +120          450                                        4         200         +127          450                                        5A        303         +240          225                                        6         366         +125          450                                        7         220         +125          600                                        8         300         +128          600                                        1A        300         +225          375                                        10        198         +190          215                                        11        300         +163          450                                        13        220         +131          220                                        15        555          +60          (500)                                      16        1013        +185          (675)                                      17B       250         +135          557                                        18        300         +165          (300)                                      19         40         +145           45                                        20G       125         +177          125                                        21C       168         +130          225                                        22D       180         +130          135                                        23B       18O         +28O          180                                        ______________________________________                                          A. Values in parentheses are the highest nontoxic dose whether the             LD.sub.20 was not determined.                                            

EXAMPLE 28 Lymphocytic Leukemia L1210 Test

The protocol for this test is identical to that for P388/0, except that the number of L1210 cells implanted on day 0 is ˜105/mouse. The mouse CD-2-F1 strain is used, and the criterion for activity is T/C×100≧125%. Results of L1210 testing are summarized in Table II below.

                  TABLE II                                                         ______________________________________                                         Screening Results for L1210                                                                           T/C × 100%                                                      Dose     Excluding 30 day                                        Compound No.  (mg/kg)  Survivors                                               ______________________________________                                         1A            150      +129                                                    ______________________________________                                    

EXAMPLE 29 Melanotic Melanoma B16

B6C3-F1 mice of the same sex, weighing 20+3 g, are used for this test. A suspension of B16 cells is prepared from a non-necrotic portion of solid tumor tissue obtained from a passage mouse. One gram of tumour is homogenized in 9 mL ice-cold Earle's salts solution and filtered through 1000 mesh screen to remove debris. 0.5 mL of the resulting brei is injected intraperitoneally into each animal. Dosing is carried out as in the P388/0 and L1210 tests. Days of death are recorded for a 60 day period, and T/C ratio calculated as in the P388/0 and L1210 tests. The criterion for activity is T/C×100≧125%. The results of B16 testing are summarized below in Table III.

                  TABLE III                                                        ______________________________________                                         Screening Results for B16 Melanoma                                                                    T/C × 100%                                        Compound of   Dose     Excluding 60 day                                        Example No.   (mg/kg)  Survivors                                               ______________________________________                                         5A            225      +159                                                    10            150      +133                                                    ______________________________________                                    

EXAMPLE 30 Lewis Lung Carcinoma Test

This tumor arose spontaneously in the lung of a C57B1/6 mouse and is maintained by subcutaneous passage in that strain. The solid tumor is excised aseptically and placed in sterile saline. Pieces of viable tumor tissue are minced finely with scissors and forced through a 200 mesh stainless steel screen to disaggregate the tumor cells into a suspension. 10⁶ Viable cells and injected intravenously into the tail vein of BD-F₁, mice of the same sex weighing 20±3 g. In each test, several dose levels which bracket the LD₂₀ for the compound are evaluated. Ten animals are included in each dose level group, and twenty animals in the untreated control group. The test compounds are prepared and aministered as in the P388/0 protocol. The day of death for each animal is recorded, the median identified for each group and the ratios of median survival time for treated (T)/control (C) groups are calculated. The criterion for activity is T/C×100≧140%. The results of Lewis Lung testing are summarized in Table IV.

                  TABLE IV                                                         ______________________________________                                         Screening Results for Lewis Lung                                                                      T/C × 100%                                                      Dose     Excluding 60 day                                        Compound No.  (mg/kg)  Survivors                                               ______________________________________                                         1B            150      208                                                     ______________________________________                                    

EXAMPLE 31 Herpes simplex 1/vero Test

Antiviral testing against Herpes simplex 1/vero was done using plaque inhibition methods as outlined in P. Collins and D. J. Bauer, Proc. N.Y. Acad. Sci. 284, 49 (1977) and by plaque reduction methods as outlined in P. Collins and D. J. Bauer, J. Antimicrobiol Chemotherapy 3, Supplement A, 73, (1977). The column headings labeled Score, Toxicity, and Zone of Inhibition refer to the plaque inhibition screen while the IC₅₀ heading to the plaque reduction screen.

                  TABLE V                                                          ______________________________________                                         Results of Antiviral Screening Against Herpes simplex 1/vero                   Compound of                  Zone of                                           Example No.                                                                              Score.sup.A                                                                             Toxicity  Inhibition.sup.B                                                                        IC.sub.50 B                              ______________________________________                                          6        -2       Y                                                           16        -4       Y                  45                                       18        -3       Y         30(ST19)                                          ______________________________________                                          A. Score Code: 0 = no inhibition                                               -1 = 1-25% inhibition                                                          -2 = 26-50% inhibition                                                         -3 = 51-75% inhibition                                                         -4 = 76-100% inhibition                                                        B. ST = slight toxicity,                                                       T = toxic,                                                                     VT = very toxic                                                          

Antibacterial Screening

Antibacterial testing against Mycoplasma smegmatis (S3264) and Streptococcus pyogens (CN10) was done with slight modifications using standard agar dilution assays as outlined in Manual of Clinical Microbiology, Second Ed., E. H. Lennette, E. H. Spaulding and J. P. Truant Eds., American Society for Microbiology, Washington, DC, 1974.

EXAMPLE 32 Mycoplasma smegmatis Test

                  TABLE VI                                                         ______________________________________                                         Results of Antibacterial Screening Against                                     Mycoplasma smegmatis (S3264)                                                          Compound MIC                                                                   Example No.                                                                             (mg/L)                                                         ______________________________________                                                2A       ≦5                                                             3        <5                                                                    5A        3                                                                    6        10                                                                    7        ≦5                                                             8        10                                                                    1A       ≦5                                                             9        10                                                                    10       >50                                                                   11       10                                                                    12       >50                                                                   13        5                                                                    14       10                                                                    15       ≦10                                                            18       ≦10                                                            19       10                                                             ______________________________________                                    

EXAMPLE 33 Streptococcus pyrogens Testing

                  TABLE VII                                                        ______________________________________                                         Results of Antibacterial Testing Against                                       Streptococcus pyogenes (CN10)                                                         Compound of                                                                             MIC                                                                   Example No.                                                                             (mg/L)                                                         ______________________________________                                                2A       10                                                                    3        10                                                                    5A        3                                                                    9        10                                                                    10        5                                                                    11        5                                                                    13        5                                                                    14       ≦5                                                             18       30                                                             ______________________________________                                    

EXAMPLE 34 Candida albicans Testing

Antifungal testing against Candida albicans (CN1863) was done with slight modifications using a combination of broth and agar dilution assays as outlined in Laboratory Handbook of Medical Mycology, Chapter 6, pages 441-446, M. R. McGinnis, Academic Press, New York, NY, 1980.

                  TABLE VIII                                                       ______________________________________                                         Results of Antifungal Screening Against                                        Candida albicans (CN1863)                                                             Compound of                                                                             MIC                                                                   Example No.                                                                             (mg/L)                                                         ______________________________________                                                1A       50                                                                    2A       10                                                                    3        30                                                                    5A       50                                                                    6        50                                                                    7        50                                                                    8        50                                                                    9        10                                                                    10       >50                                                                   11       50                                                                    12       >50                                                                   13       10                                                                    14       50                                                                    15       >50                                                                   19       30                                                             ______________________________________                                          Medium: Wellcotest* sensitivity test agar plus 7% lysed horse blood.     

EXAMPLE 35 Trichomonas vaginalis Testing

Antiprotozoal testing against Trichomonas vaginalis was done using methods outlined by R. M. Michaels in Advances in Chemotherapy, 3, 39-108 (1968).

                  TABLE IX                                                         ______________________________________                                         Results of Antiprotozoal Testing Against                                       Trichomonas vaginalis (in vitro)                                               Compound of     Dose                                                           Example No.     (mg/L)  Result.sup.A                                           ______________________________________                                         1A              40      -4                                                     2A              40      -3                                                     3               6.25    -4                                                     5A              40      -3                                                     6               40      -4                                                     9               40      -2                                                     11              40      -4                                                     ______________________________________                                          (Stenton or Modified Diamond's medium)                                         A. Screen Code 0 = no inhibition                                               -1 = 1-25% inhibition                                                          -2 = 26-50% inhibition                                                         -3 = 51-75% inhibition                                                         -4 = 76-100% inhibition                                                  

EXAMPLE 36 Nippostrongylus brasiliensis Testing

Anthelmintic testing against Nippostrongylus brasiliensis was done using methods as outlined in D. C. Jenkins, R. Armitage, and T. S. Carrington, Zetschrift fur Parasitenkunde 63, 261-269 (1980).

                  TABLE X                                                          ______________________________________                                         Results of Anthelmintic Screening Against                                      Nippostrongylus brasiliensis                                                   (Immature - free living stages)                                                       Compound of                                                                             MIC                                                                   Example No.                                                                             (mg/L)                                                         ______________________________________                                                2A       10                                                                    3         1                                                                    4        10                                                                    5A       100                                                                   1A       50                                                                    9        50                                                                    14       50                                                                    13       50                                                                    11       ≧50                                                            10       ≧50                                                     ______________________________________                                    

EXAMPLE 37 Eimeria tenella Testing

Antiprotozoal testing against Eimeria tenella was done using methods outlined in V. S. Latter and D. Wilson, Parasitology 79, 169 (1979).

                  TABLE XI                                                         ______________________________________                                         Results of Antiprotozoal Screening Against                                     Eimeria tenella (in vitro)                                                     Compound of     Dose                                                           Example No.     (mg/L)  Result.sup.A                                           ______________________________________                                         2A              5       -2                                                     14              0.31    -2                                                     13              5       -2                                                     12              5       -4                                                     11              5       -4                                                     10              0.37    -4                                                     ______________________________________                                          A. Screen Code 0 = no inhibition                                               -1 = 1-25% inhibition                                                          -2 = 26-50% inhibition                                                         -3 = 51-75% inhibition                                                         -4 = 76-100% inhibition                                                  

EXAMPLE 38 Brugia pahangi Testing

Anthelmintic testing against Brugia pahangi was done using methods outlined in D. A. Denham et al., Transactions of the Royal Society of Tropical Medicine and Hygiene 73, 673-676 (1979).

                  TABLE XII                                                        ______________________________________                                         Results of Screening Against Brugia pahangi microfilaria (in vitro)            Compound of                                                                               Dose                  MIC                                           Example No.                                                                               (mg/L)       Result.sup.A                                                                            (mg/L)                                        ______________________________________                                         2A         3.1          -4       3.10                                          3          0.78         -4       0.78                                          4          12.5         -2                                                     12         12.5         -2                                                     ______________________________________                                          A. Screen Code 0 = no inhibition                                               -1 = 1-25% inhibition                                                          -2 = 26-50% inhibition                                                         -3 = 51-75% inhibition                                                         -4 = 76-100% inhibition                                                  

EXAMPLE 39 LD₅₀ Tests

                  TABLE XIII                                                       ______________________________________                                         LD.sub.50 Values for Selected Compounds                                        (IP single dose - CD.sub.1 Male Mouse)                                                Compound of                                                                             LD.sub.50                                                             Example No.                                                                             (mg/kg)                                                        ______________________________________                                                5A       160                                                                   6        350                                                                   1A       350                                                                   9        350                                                                   14       130                                                                   13       160                                                                   11       250                                                                   10       160                                                            ______________________________________                                    

EXAMPLE 40 Formulation Examples

    ______________________________________                                         A. TABLET                                                                      ______________________________________                                         Compound of Formula I                                                                              500.0      mg                                              Pregelatinized Corn Starch                                                                         60.0       mg                                              Sodium Starch Glycolate                                                                            36.0       mg                                              Magnesium Stearate  4.0        mg                                              ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed with the powdered excipients, pregelatinized corn starch and sodium starch glycolate. The powders are wetted with purified water to form granules. The granules are dried and mixed with the magnesium stearate. The formulation is then compressed into tablets weighing approximately 600 mg each.

    ______________________________________                                         B. TABLET                                                                      ______________________________________                                         Compound of formula (I)                                                                           500.0       mg                                              Corn Starch        70.0        mg                                              Lactose            83.8        mg                                              Magnesium Stearate 4.2         mg                                              Polyvinylpyrrolidone                                                                              14.0        mg                                              Stearic Acid       28.0        mg                                              ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed with the powdered excipients, corn starch and lactose. The powders are wetted with a solution of polyvinylpyrrolidone dissolved in purified water and denatured alcohol to form granules. The granules are dried and mixed with the powdered stearic acid and magnesium stearate. The formulation is then compressed into tablets weighing approximately 700 mg each.

    ______________________________________                                         C. CAPSULES                                                                    ______________________________________                                         Compound of formula (I)                                                                           500.0       mg                                              Corn Starch        50.0        mg                                              Magnesium Stearate 3.0         mg                                              ______________________________________                                    

The finely divided compound of formula (I) is mixed with powdered corn starch and wetted with denatured alcohol to densify the powder. The dried powder is mixed with stearic acid and filled into hard-shell gelatin capsules.

    ______________________________________                                         D. SYRUP                                                                       ______________________________________                                         Compound of formula (I)                                                                           250.0       mg                                              Ethanol            250.0       mg                                              Glycerin           500.0       mg                                              Sucrose            3,500.0     mg                                              Flavoring Agent    q.s.                                                        Coloring Agent     q.s.                                                        Preserving Agent   0.1%                                                        Purified Water q.s. to                                                                            5.0         mL                                              ______________________________________                                    

The compound of formula (I) is dissolved in the ethanol, glycerin, and a portion of the purified water. The sucrose and preserving agent are dissolved in another portion of hot purified water, and then the coloring agent is added and dissolved. The two solutions are mixed and cooled before the flavoring agent is added. Purified water is added to final volume. The resulting syrup is thoroughly mixed.

    ______________________________________                                         E. IV INJECTION                                                                ______________________________________                                         Compound of formula (I)                                                                          5.0 mg                                                       Glycerin          q.s. for isotonicity                                         Preservative      0.1%                                                         Hydrochloric Acid or                                                                             as needed for                                                Sodium Hydroxide  pH adjustment                                                Water for Injection                                                                              q.s. to 1 mL                                                 ______________________________________                                    

The compound of formula (I) and preservative is added to the glycerin and a portion of the water for injection. The pH is adjusted with hydrochloric acid or sodium hydroxide. Water for injection is added to final volume and solution is complete after thorough mixing. The solution is sterilized by filtration through a 0.22 micrometer membrane filter and aseptically filled into sterile 10 mL ampules or vials. 

What is claimed is:
 1. A compound of the formula: ##STR11## where R¹⁹ is hydrogen or methyl and R²⁰ is hydrogen, methyl or ethyl or a pharmaceutically acceptable acid addition salt thereof.
 2. The compound of claim 1 where R²⁰ is methyl.
 3. 2-methyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol or a pharmaceutically acceptable acid addition salt thereof.
 4. A compound of the formula: ##STR12## 